The gene encoding the receptor tyrosine kinase (RTK) HER2/neu/ErbB2 is an important human breast cancer oncogene, and a validated therapeutic target. We hypothesize that optimal development and use of ErbB2-targeted therapeutics will require a thorough understanding of the normal biological functions of ErbB2 and its regulation by interactions with other ErbB family receptors. Aim 1 continues our analysis of normal functions of ErbB2 and ErbBS in mammary gland development. Aim 2 investigates a new hypothesis in which excessive signaling through ErbB2 drives genomic instability in breast cancer through actuation of DNA checkpoint signaling and selection for checkpoint bypass. Aim 3 will evaluate phosphorylation markers for measuring for ErbB and pathway activation in human cancer n the best-case setting of core biopsies. The significance of these studies extends well beyond breast cancer, since the Epidermal Growth Factor Receptor (EGFR) and ErbB2 are mutated or overexpressed in many types of adenocarcinoma. Since ErbBs are forefront targets for new RTK inhibitors in cancer treatment, success of our efforts to merge ErbB biology with tumor studies will pave the way for similar approaches to cancers caused by other RTKs.